tbuckley/cabot-search huggingface dataset:
Abstract 3879: High dimensional analysis of tumor microenvironment and heterogeneity in FIGO IB endometrial carcinomas using imaging mass cytometry
Authors: Hilde Eide Lien, Hege Fredriksen Berg, Erling Andre Hoivik, Jone Trovik, Ingfrid Salvesen Haldorsen, Lars Andreas Akslen, Camilla Krakstad
Journal: Cancer Research (2022)

Abstract Patients with localized endometrial carcinomas (FIGO IA and IB) have a 5-year relative survival rate of &amp;gt; 90%. Still, some patients with an expected good prognosis experience recurrence of disease which dramatically reduces survival rates. Currently, we lack the knowledge to predict which patients will get recurrence. We used Imaging Mass Cytometry to examine 27 proteins in tissue microarrays of 36 primary FIGO IB endometrial carcinomas, of which 17 later recurred. High dimensional images were segmented to extract single-cell information for each tumor. Distinct epithelial-, stromal- and immune cell types of the tumor microenvironment were identified and phenotyped, using protein expression intensities and unsupervised cell clustering. Neighboring cells of CD8+ cells were extracted and phenotyped. In non-recurrent tumors, more cytotoxic T cells were identified adjacent to two epithelial cell populations characterized by high vimentin and progesterone receptor expression (p &amp;lt; 0.01 and p = 0.02). Tumors that were enriched for vimentin showed significantly better recurrence-free survival than tumors with low vimentin or high alpha-smooth muscle actin (a-SMA) signal (p = 0.026). This study reveals distinct characteristics in the microenvironment of low stage tumors that may aid in identifying high-risk patients. Further, the study provides new insight on the pathogenic processes involved in tumor progression of endometrial cancer. Citation Format: Hilde Eide Lien, Hege Fredriksen Berg, Erling Andre Hoivik, Jone Trovik, Ingfrid Salvesen Haldorsen, Lars Andreas Akslen, Camilla Krakstad. High dimensional analysis of tumor microenvironment and heterogeneity in FIGO IB endometrial carcinomas using imaging mass cytometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3879.
Abstract 2783: Increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in normal colonic mucosa with imipridone ONC201/TIC10 treatment: A potential biomarker for chemoprevention studies
Authors: Alexander G. Raufi, Arielle De La Cruz, Andrew George, Sean Hacking, Venkateshwar Madka, Varun Prabhu, Howard Safran, Lanlan Zhou, Dean Brenner, Chinthalapally V. Rao, Wafik S. El-Deiry
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States and currently the most effective method at reducing risk of death is through screening. Although these strategies have reduced the incidence of CRC, they are invasive, costly, and have low rates of compliance. Chemoprevention aims to prevent or delay the onset of CRC through eradication or prevention of precursor colonic adenomas, ideally with affordable and nontoxic drugs. The imipridone ONC201, which induces apoptosis, in part, through upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), is currently undergoing preclinical evaluation as a potential chemopreventive agent. In preclinical models, we found that treatment with ONC201 is capable of increasing TRAIL expression in normal cells and can improve tumor suppression through immune surveillance by the innate immune system. To further assess potential biomarkers of response to ONC201, we evaluated expression of TRAIL and death receptor 5 (DR5), as well as markers related to cellular stemness such as LGR5 in colonic mucosa obtained from mice treated with ONC201 and vehicle controls. In this study, 16-week-old female C57BL/6 mice were administered vehicle or ONC201 50mg/kg (n=11) body weight by oral gavage twice a week for a total of five doses. Both immunohistochemistry and western blotting were used to evaluate differential expression of various potential biomarkers in both fresh frozen and FFPE colonic tissue. Using western blotting we found a significant increase in TRAIL expression in normal colonic mucosa obtained from mice treated with ONC201 as compared to vehicle controls. This finding was further validated using immunohistochemistry. Other markers, such as DR5 appeared unaffected with treatment. As efforts are currently underway to develop a CRC chemoprevention trial using ONC201, TRAIL may represent a biomarker of interest. Further analysis of stemness markers, as well as serum analyses are currently in process and may reveal other potential biomarkers for use in chemoprevention trial development. Citation Format: Alexander G. Raufi, Arielle De La Cruz, Andrew George, Sean Hacking, Venkateshwar Madka, Varun Prabhu, Howard Safran, Lanlan Zhou, Dean Brenner, Chinthalapally V. Rao, Wafik S. El-Deiry. Increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in normal colonic mucosa with imipridone ONC201/TIC10 treatment: A potential biomarker for chemoprevention studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2783.
Abstract LB056: The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution
Authors: Ajit Johnson Nirmal, Zoltan Maliga, Tuulia Vallius, Brian Quattrochi, Alyce Chen, Connor Jacobson, Roxanne Pelletier, Clarence Yapp, Raquel Arias-Camison, Yu-An Chen, Christine Lian, George F. Murphy, Sandro Santagata, Peter K. Sorger
Journal: Cancer Research (2022)

Abstract Cutaneous melanoma is a highly immunogenic malignancy, surgically curable at early stages, but life-threatening when metastatic. The spatial organization of the tumor ecosystem during early-stage melanoma is not well understood. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially-resolved micro-region transcriptomics to study immune evasion and immunoediting in primary melanoma. We collected highly multiplexed single-cell data from 70 distinct histological regions from 13 specimens (patients) selected to have multiple progression-associated histologies within a single resection. These histologies range from pre-malignant fields in which melanocytic atypia represents the first steps in cancer initiation to non-invasive (radial growth phase) and invasive (vertical growth phase) primary melanoma that eventually gives rise to disseminated disease. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and primary invasive tumor. Hallmarks of immunosuppression were detectable as early as the melanoma precursor stage, and when tumors become locally invasive, a consolidated and spatially restricted environment with multiple overlapping immunosuppressive mechanisms forms along the tumor-stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1 and by PDL1-expressing macrophages and dendritic cells engaging activated T cells. However, only a few millimeters away, T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can co-exist within a few millimeters of each other in a single specimen. Multiplexed single-cell imaging and micro-region mRNA profiling link morphological and molecular features of tumor evolution within and across primary cancer specimens, revealing highly localized programs of immune and tumor cell communication via paracrine cytokine signaling and direct cell-cell contact. Citation Format: Ajit Johnson Nirmal, Zoltan Maliga, Tuulia Vallius, Brian Quattrochi, Alyce Chen, Connor Jacobson, Roxanne Pelletier, Clarence Yapp, Raquel Arias-Camison, Yu-An Chen, Christine Lian, George F. Murphy, Sandro Santagata, Peter K. Sorger. The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB056.
Abstract 2645: Targeting mRNA processing pathways in ovarian cancer with a small molecule inhibitor
Authors: Dhanir Tailor, Chia-Feng Tsai, Alexander Honkala, Wenqi Li, Tao Liu, Tanja Pejovic, Sanjay V. Malhotra
Journal: Cancer Research (2022)

Abstract mRNA processing related pathways, including spliceosome and ribosome are over-expressed and unregulated in cancer cells. To investigate the mRNA processing pathways in patient samples, we performed a comprehensive, tandem mass tag (TMT) labeling-based proteome and phosphoproteome profiling of the normal and ovarian cancerous tissues from patients treated with different chemotherapy revealed that malignant cells have overexpression of mRNA processing pathways compared to normal cells. For this analysis, equal amount of tissues were homogenized, and tissue lysates were collected and processed for the quantitative proteomics and phosphoproteomics analysis. KEGG pathway enrichment analysis revealed that spliceosome, basal transcription factors, mRNA surveillance, ribosome and ribosome biogenesis in eukaryotes pathways are upregulated in cancer cells compared to control. On other hand, pathways associated with metabolism and fatty acid biosynthesis were downregulated in malignant cells. Moreover, kinase Enrichment Analysis shows that CDK2, ATM, ATR, and MAPK associated kinases are upregulated in cancer cells compared to normal. Based on proteome analysis of patient samples, we investigated the pharmacological inhibition of Y-box binding protein 1 (YB-1). This is an RNA binding protein and key regulator of pre-mRNA alternative splicing and processing. We recently showed that a natural product-derived small molecule (SU056) inhibits YB-1 activity. We found that SU056 binds to the YB-1 and blocks the RNA binding pocket. Proteomics results suggest that treatment with this drug strongly inhibits the spliceosome pathway. SU056 treatment arrests the ovarian cancer cells in G1 phase and inhibits the CDK2 and Cyclin E. SU056 inhibits the tumor progression and metastasis in the ID8 mice model and sensitizes the OVCAR8 NSG mice model for paclitaxel treatment. Our study provides a compelling case for YB-1 inhibition using SU056 as a potential therapy for ovarian cancer. Citation Format: Dhanir Tailor, Chia-Feng Tsai, Alexander Honkala, Wenqi Li, Tao Liu, Tanja Pejovic, Sanjay V. Malhotra. Targeting mRNA processing pathways in ovarian cancer with a small molecule inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2645.
Abstract 3082: Leveraging 3D organoids to identify molecular changes underlying HNSC initiation and development
Authors: Robert Agee, Samuel Flashner, Masataka Shimonosono, Andres Klein-Szanto, Hiroshi Nakagawa
Journal: Cancer Research (2022)

Abstract Head and neck squamous cell carcinoma (HNSC) is a devastating disease accounting for 570,000 newly diagnosed cases and resulting in 344,000 deaths annually. HNSC arises from its histological precursor lesion, squamous dysplasia (HNSD); however, most patients are diagnosed with late-stage HNSC with no prior identification of pre-malignant disease. Earlier diagnosis and intervention could ameliorate the outsized burden of HNSC; therefore, there is an urgent unmet need to characterize the molecular changes underlying progression through HNSD to HNSC. To identify novel therapeutic targets or biomarkers that predict progression to HNSC, we have generated a three dimensional (3D) organoid library derived from dysplastic oral tissue harvested from mice treated with 4-Nitriquinoline N-oxide (4-NQO), a potent mimetic of tobacco smoke. Through RNA sequencing analysis of these organoids, we have identified two distinct gene expression states that accompany either early or late dysplasia. By performing gene set enrichment analysis of these two distinct gene signatures, we have identified c-Jun N-terminal Kinase (JNK) signaling as a potential biomarker that predicts or progression from HNSD to HNSC. Together, we have identified the salient transcriptional changes that accompany progression through the histological precursor lesion of HNSC. This study positions JNK signaling as a potential biomarker or therapeutic target for early intervention during the treatment of a deadly disease. Citation Format: Robert Agee, Samuel Flashner, Masataka Shimonosono, Andres Klein-Szanto, Hiroshi Nakagawa. Leveraging 3D organoids to identify molecular changes underlying HNSC initiation and development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3082.
Abstract 5821: Enhanced tumorigenesis in a novel miR-216a knockout/KPC mouse model of pancreatic cancer
Authors: Andrew A. Brock, Katherine Powell, Thomas D. Schmittgen, Lorenzo F. Sempere
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) originates from both ductal and acinar cells of the pancreas. The highly abundant and acinar cell-enriched miR-216a is reduced during in vitro acinar ductal metaplasia (ADM), throughout PanIN progression, during the development of pancreatitis in mice and humans, and during development of mouse and human PDAC. To investigate the contribution of miR-216a in the development of PDAC, we generated a miR-216a germline knockout mouse (216aKO) via CRISPR genetic editing of a minimal and precise deletion of the miR-216a precursor sequence without affecting the host gene. We crossed this 216aKO mouse to the LSL-KrasG12D; LSL-Trp53Flox/+; Pdx1Cre/+ (KPC) mice to produce a transgenic mouse with an activating Kras mutation, p53 deletion, and knockout of miR-216a (referred to here as miR216aKPC). miR216aKPC displayed an increase in tumor progression compared to KPC and had reduced survival - median 15 weeks miR216aKPC vs. 25 weeks for KPC. miR216aKPC produced lung metastasis by 12 weeks of age which were not present in the lungs of similarly aged KPC mice. Transfection of miR-216a mimetic oligo into cell lines derived from KPC or 216aKPC mice did not reduce viability or alter cellular morphology, suggesting that a potential tumor suppressive role of miR-216a functions during the early stages of PDAC development. A three dimensional ADM assay using acinar cells derived from both mouse and human pancreata will be applied to investigate the contributions of miR-216a on the development of ADM and cell polarity. To discover miR-216a target genes that are responsible for the increased tumorigenesis, cell lines derived from miR216aKPC will be transfected with miR-216a mimetic or scrambled control oligo followed by RNA sequencing. Our results thus far suggest a tumor suppressive role for miR-216a in the early development of PDAC and future studies will investigate molecular and cellular mechanisms driving acinar cell-induced PDAC. Citation Format: Andrew A. Brock, Katherine Powell, Thomas D. Schmittgen, Lorenzo F. Sempere. Enhanced tumorigenesis in a novel miR-216a knockout/KPC mouse model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5821.
Abstract 6399: SP in relation to NK1R and Ki67 predicts survival in hormone receptor negative breast cancer
Authors: Maha S. Al-Keilani, Rana Elstaty, Mohammad A. Alqudah
Journal: Cancer Research (2022)

Abstract Background: Substance P (SP) is a tachykinin that has been implicated in carcinogenesis in several types of cancer through binding to neurokinin 1 receptor (NK1R). This study aimed to investigate the expression levels of SP and NK1R in hormone receptor negative (HR -ve) versus positive (HR +ve) breast cancer tissues and their relationship with clinicopathological characteristics of patients, Ki-67 index, and overall survival rate. Methods: Immunohistochemical expression levels of SP, NK1R and Ki-67 were measured in 144 paraffin-embedded breast cancer tissues (77 HR -ve and 67 HR +ve). SP and NK1R were scored semiquantitatively, while Ki-67 was obtained by the percentage of total number of tumor cells with nuclear staining. The optimal cutoff value for SP, NK1R and Ki-67 were assessed by Cutoff Finder. Pearson Chi-square (χ2) and Fisher’s exact tests were used to compare the staining scores between groups. ANOVA and student’s t-test were used to compare group means. Kaplan-Meier method with log-rank test was used for survival analysis. Results: High expression of SP, NK1R and Ki-67 was observed in 41%, 36.8% and 38.9% of cases, respectively. Association analyses revealed that SP expression in HR -ve breast cancer was higher in pN3 tumors (p=0.002), positive axillary lymph node metastasis (p=0.003), and high NK1R expression (p=0.010). In HR+ve breast cancer, SP was lower in HER2 positive tumors (p=0.001). Regarding NK1R, the association analysis showed that low NK1R expression level in HR +ve tumors was related to stage IV (p=0.023), pN1 (p=0.006), and low Ki-67 index (p=0.038). Survival analysis revealed that high SP level negatively impacted overall survival in HR-ve tumors that had low NK1R level (p=0.021). Moreover, high SP negatively impacted overall survival in HR-ve tumors that had low Ki-67 level (p=0.005). Nevertheless, NK1R expression did not impact survival in HR-ve or HR+ve cases despite stratification by SP and Ki-67 expression (p&amp;gt;0.05). Conclusion: Up to our knowledge, this is the first study to investigate the prognostic potential of SP and NK1R in breast cancer. Combined expression levels of SP and NK1R or Ki-67 could be used to predict survival in breast cancer patients with HR-ve tumors. Our findings suggest the potential role of SP and NK1R as therapeutic targets in breast cancer. Citation Format: Maha S. Al-Keilani, Rana Elstaty, Mohammad A. Alqudah. SP in relation to NK1R and Ki67 predicts survival in hormone receptor negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6399.
Abstract 1312: Pro-survival lipid metabolism activates intracellular complement signaling to induce inflammasome-mediated tumor metastasis
Authors: Alhaji H. Janneh, Besim Ogretmen
Journal: Cancer Research (2022)

Abstract Tumor metastasis remains one of the major causes of cancer-related deaths in patients with solid tumors. Mechanisms by which metabolic alterations regarding pro-survival lipid signaling activation in inducing cancer cell migration and metastasis are largely unknown. Here, we demonstrate that sphingosine 1-phosphate (S1P) metabolism activates endogenous complement signaling for inducing tumor metastasis via inducing inflammasome-mediated pro-inflammation. Our studies using molecular, pharmacologic, and genetic tools showed that activation of S1P and S1P receptor 1 (S1P/S1PR1) induces tumor metastasis via enhanced intracellular complement signaling by the regulation of the C3-PPIL1 complex and subsequent inflammasome activation in cancer cells and in vivo xenograft-derived tumors. Citation Format: Alhaji H. Janneh, Besim Ogretmen. Pro-survival lipid metabolism activates intracellular complement signaling to induce inflammasome-mediated tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1312.
Methylation of the Hippo effector YAP by the methyltransferase SETD7 drives myocardial ischaemic injury: a translational study
Authors: Samuele Ambrosini, Fabrizio Montecucco, Detmar Kolijn, Daniela Pedicino, Alexander Akhmedov, Shafeeq A Mohammed, Melissa Herwig, Era Gorica, Petra L Szabó, Lukas Weber, Giulio Russo, Ramona Vinci, Christian M Matter, Giovanna Liuzzo, Peter J Brown, Fabio M V Rossi, Giovanni G Camici, Sebastiano Sciarretta, Antonio P Beltrami, Filippo Crea, Bruno Podesser, Thomas F Lüscher, Attila Kiss, Frank Ruschitzka, Nazha Hamdani, Sarah Costantino, Francesco Paneni
Journal: Cardiovascular Research (2022)

Methylation of non-histone proteins is emerging as a central regulatory mechanism in health and disease. The methyltransferase SETD7 has shown to methylate and alter the function of a variety of proteins in vitro; however, its function in the heart is poorly understood. The present study investigates the role of SETD7 in myocardial ischaemic injury.Experiments were performed in neonatal rat ventricular myocytes (NRVMs), SETD7 knockout mice (SETD7-/-) undergoing myocardial ischaemia/reperfusion (I/R) injury, left ventricular (LV) myocardial samples from patients with ischaemic cardiomyopathy (ICM), and peripheral blood mononuclear cells (PBMCs) from patients with ST-elevation MI (STEMI). We show that SETD7 is activated upon energy deprivation in cultured NRVMs and methylates the Hippo pathway effector YAP, leading to its cytosolic retention and impaired transcription of antioxidant genes manganese superoxide dismutase (MnSOD) and catalase (CAT). Such impairment of antioxidant defence was associated with mitochondrial reactive oxygen species (mtROS), organelle swelling, and apoptosis. Selective pharmacological inhibition of SETD7 by (R)-PFI-2 restored YAP nuclear localization, thus preventing mtROS, mitochondrial damage, and apoptosis in NRVMs. In mice, genetic deletion of SETD7 attenuated myocardial I/R injury, mtROS, and LV dysfunction by restoring YAP-dependent transcription of MnSOD and CAT. Moreover, in cardiomyocytes isolated from I/R mice and ICM patients, (R)-PFI-2 prevented mtROS accumulation, while improving Ca2+-activated tension. Finally, SETD7 was up-regulated in PBMCs from STEMI patients and negatively correlated with MnSOD and CAT.We show a methylation-dependent checkpoint regulating oxidative stress during myocardial ischaemia. SETD7 inhibition may represent a valid therapeutic strategy in this setting.
NELL1 Regulates the Matrisome to Promote Osteosarcoma Progression
Authors: Qizhi Qin, Mario Gomez-Salazar, Robert J. Tower, Leslie Chang, Carol D. Morris, Edward F. McCarthy, Kang Ting, Xinli Zhang, Aaron W. James
Journal: Cancer Research (2022)

Sarcomas produce an abnormal extracellular matrix (ECM), which in turn provides instructive cues for cell growth and invasion. Neural EGF like-like molecule 1 (NELL1) is a secreted glycoprotein characterized by its nonneoplastic osteoinductive effects, yet it is highly expressed in skeletal sarcomas. Here, we show that genetic deletion of NELL1 markedly reduces invasive behavior across human osteosarcoma (OS) cell lines. NELL1 deletion resulted in reduced OS disease progression, inhibiting metastasis and improving survival in a xenograft mouse model. These observations were recapitulated with Nell1 conditional knockout in mouse models of p53/Rb-driven sarcomagenesis, which reduced tumor frequency and extended tumor-free survival. Transcriptomic and phosphoproteomic analyses demonstrated that NELL1 loss skews the expression of matricellular proteins associated with reduced FAK signaling. Culturing NELL1 knockout sarcoma cells on wild-type OS-enriched matricellular proteins reversed the phenotypic and signaling changes induced by NELL1 deficiency. In sarcoma patients, high expression of NELL1 correlated with decreased overall survival. These findings in mouse and human models suggest that NELL1 expression alters the sarcoma ECM, thereby modulating cellular invasive potential and prognosis. Disruption of NELL1 signaling may represent a novel therapeutic approach to short-circuit sarcoma disease progression.NELL1 modulates the sarcoma matrisome to promote tumor growth, invasion, and metastasis, identifying the matrix-associated protein as an orchestrator of cell-ECM interactions in sarcomagenesis and disease progression.